P374. Secondary infliximab treatment failure in Crohn's disease: therapeutic implications of measuring drug and anti-drug antibodies by three different binding assays
C. Steenholdt1, J. Brynskov1, O. Thomsen1, L. Munck2, J. Fallingborg3, L. Christensen4, G. Pedersen5, J. Kjeldsen6, K. Bendtzen7, M. Ainsworth1, 1Herlev Hospital, Dept of Gastroenterology, Herlev, Denmark, 2Køge Hospital, Dept of Medical Gastroenterology, Køge, Denmark, 3Aalborg Hospital, Dept of Medical Gastroenterology, Aalborg, Denmark, 4Aarhus Hospital, Dept of Hepatology and Gastroenterology V, Aarhus, Denmark, 5Hvidovre Hospital, Dept of Gastroenterology, Hvidovre, Denmark, 6Odense Hospital, Dept of Medical Gastroenterology S, Odense, Denmark, 7Rigshospitalet, University Hospital of Copenhagen, Institute for Inflammation Research, Dept. of Infectious Diseases and Rheumatology, Copenhagen, Denmark
Proposed algorithms for therapeutic interventions in Crohn's disease patients with secondary infliximab (IFX) failure are based on serum concentration measurements of IFX and anti-IFX antibodies (Abs). Several analytical techniques are currently used for this purpose. We investigated how classification of IFX failures is affected by choice of assay.
IFX and anti-IFX Abs were measured in 67 Crohn's disease patients at time of secondary IFX failure (55 luminal, 6 fistulizing, 6 both; CDAI mean 300; draining perianal fistulas mean 2; IFX duration mean 630 days) using radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and homogeneous mobility shift assay (HMSA). Previously established clinical efficacy cut-off levels were used for classification of mechanism of secondary IFX failure (IFX: 0.5 µg/ml in RIA, above detection limit in ELISA, 3 µg/ml in HMSA. Anti-IFX Abs: Above detection limit in all assays).
IFX was above detection limit in 88% of patients by RIA, 75% by ELISA, and 88% by HMSA. Anti-IFX Abs were detectable in 27%, 9%, and 34%, respectively. All assays showed linear correlations (Person r for IFX: 0.94–0.97; Pearson r for Anti-IFX 0.77–0.82). Algorithms for classification of IFX failures operate with three distinct mechanisms and thus proposed interventions: 1) Immunogenicity (positive anti-IFX Abs; low IFX), 2) pharmacokinetics (negative anti-IFX Abs; low IFX), 3) pharmacodynamics (negative anti-IFX Abs; high IFX). RIA and ELISA agreed on this classification in 78% of patients, RIA and HMSA in 72%, and ELISA and HMSA in 58%. A sizable fraction of patients (49–75%) were classified by all three assays as having treatment failure due to a pharmacodynamic problem. This is presumed to be caused by activation of alternative immune pathways bypassing TNF-alpha as one of the central disease mediators. Immunogenicity (9–28%) and pharmacokinetics (3–16%) occurred less frequently as a likely explanation.
IFX and anti-IFX Ab measurements by RIA, ELISA, or HMSA result in similar therapeutic interventions in most patients with secondary IFX failure. However, implications are profound for the substantial minority classified differently. IFX failure is usually caused by pharmacodynamic mechanisms, and TNF-inhibitors may have limited effect in these patients. Fluid-phase binding assays, HMSA and RIA, for IFX and anti-IFX Abs are suitable for therapeutic guidance and superior to solid phase ELISA.